| Abstract: |
The potential of raltitrexed (Tomudex(TM)) in combination with 5- fluorouracil (5-FU) as treatment for advanced colorectal cancer has been investigated in two phase I clinical trials. In the first study, raltitrexed was combined with bolus 5-FU; patients received raltitrexed as a 15-min infusion followed 24 h later by bolus 5-FU every 3 weeks. In the second study, 5-FU was administered as a weekly 24-h infusion for 5 weeks of a 6- week cycle and raltitrexed was given 15-min prior to 5-FU on days 8 and 29. The recommended dose for bolus 5-FU in combination with raltitrexed is likely to be 1200 mg/m2 as dose-limiting toxicity (DLT) of febrile neutropenia was observed at 1350 mg/m2, but escalation of raltitrexed above the dose used for single-agent use (3.0 mg/m2) continues. In the raltitrexed/infusional 5- FU study, dose escalation is also still continuing, but only in men as no DLT has been observed in men; 2 of 3 female patients had DLT of myelosuppression and diarrhoea at raltitrexed 3.0 mg/m2 and infusional 5-FU 2400 mg/m2. Raltitrexed had a significant effect on the pharmacokinetics of 5-FU irrespective of 5-FU regimen. Preliminary response data is encouraging with 53% of patients receiving raltitrexed/infusional 5-FU showing a partial response. In addition, significant disease stabilisation was observed in patients receiving raltitrexed combined with bolus 5-FU who had previously failed 5-FU therapy. Recruitment has recently commenced in two studies in which raltitrexed is combined with oral derivatives of 5-FU. In conclusion, preliminary data from these phase I studies indicate that the combination of raltitrexed and 5-FU is well tolerated and has encouraging clinical activity. |
